Avastin (Bevacizumab) for ROP shows Dangerous Late Recurrences

I have seen a significant number of retinal detachments following Avastin monotherapy.  I believe the recurrences are extremely atypical.  They show a different morphology and often a different location.  The recurrences often appear as vascular tangles and growths without any fibrous tissue and often occur well posterior to the junction of the vascular and avascular retina.  They seem to be near the original site of stage 3. The early subtle recurrences may not occur until 8 weeks following the injection!  In order to see the vascular proliferation careful examination with indirect ophthalmoscopy and 20 diopter lens are needed.  Mike Blair, MD and I, have a letter to the editor in press, describing the first detachment referred and hope to submit a series ASAP. 

I consider close observation mandatory until about 80 weeks PMA.  Many of my own cases have had reinjection or laser. 

I am working on a log without identifiers to track the regression and recurrence pattern after Avastin.  Dear readers please beware; this is a lovely treatment but still carries potential dangers.  Please use with caution. 

Publications 2011

1: Chow CC, Blair MP, Shapiro MJ. Acquired vasoproliferative retinal tumor: a
late sequela of retinopathy of prematurity. Arch Ophthalmol. 2011
Sep;129(9):1234-5. PubMed PMID: 21911679.


2: Repka MX, Tung B, Good WV, Capone A Jr, Shapiro MJ. Outcome of eyes developing
retinal detachment during the Early Treatment for Retinopathy of Prematurity
study. Arch Ophthalmol. 2011 Sep;129(9):1175-9. PubMed PMID: 21911664.


3: Kiernan DF, Al-Heeti O, Blair MP, Keenan JD, Lichtenstein SJ, Tsilou ET,
Smaoui N, Shapiro MJ. Peripheral retinal nonperfusion in septo-optic dysplasia
(de Morsier syndrome). Arch Ophthalmol. 2011 May;129(5):671-3. PubMed PMID:
21555628.


4: Hoang QV, Blair MP, Rahmani B, Galasso JM, Shapiro MJ. Multiple retinal holes
and peripheral nonperfusion in muscle-eye-brain disease. Arch Ophthalmol. 2011
Mar;129(3):373-5. PubMed PMID: 21403000.


5: Shapiro MJ, Chow CC, Karth PA, Kiernan DF, Blair MP. Effects of green diode
laser in the treatment of pediatric Coats disease. Am J Ophthalmol. 2011
Apr;151(4):725-731.e2. Epub 2011 Jan 22. PubMed PMID: 21257148.


6: Kiernan DF, Blair MP, Shapiro MJ. Neovascularization after nonaccidental
trauma. Ophthalmology. 2010 Dec;117(12):2443.e1-2. PubMed PMID: 21129574.

Avastin Paper in New England Journal of Medicine (BEAT-ROP)

I read the Avastin paper and like all studies it is imperfect. I would say more imperfect than the elegant ETROP, CRYO-ROP or STOP-ROP studies (note my personal bias here).  Nonetheless it is a major effort and accomplishment.  Looking at the literature regarding avastin in diabetes and ROP, and listening to the presentations of my many colleagues about their experience using avastin has persuaded me that that avastin has a strong positive effect on the fibrovascular proliferation of ROP.  Moreover, it is certainly much easier and less stressful to perform and locally safer than laser.  It is in many ways more conservative than laser

My real worry is that the late disease seen after the outcome measurement may lead to significant complications in some patients.  In my experience which admittedly is in extreme cases and salvage after previous laser failure, I have seem many late recurrences that would be missed by examination at 55 weeks PMA. In the study, the average treatment in zone 1 was about 35 weeks and the interval to recurrence was around 20 weeks, so at 55 weeks there would be many recurrences yet to see.  I am unhappy to leave large areas of non-perfusion in the periphery and this may be a late source of serious complications.

Now for my particular questions:

1. What was the definition of posterior zone 2?  Posterior zone 2 is not an ICROP term.
2. Was anterior zone 2 treated by laser or observed.
3. How was the author analysis done and what happened if the data sheets and photos did not line up for zone, stage or plus or recurrence. 
4. How was confirmation done
5. Need exact definition of recurrence with photographs.  Use of recurrence is hard to compute because in ETROP you had an outcome that was structural and I am not sure, how it was defined.  How about persistence?  How about 2 week skips lesions?  How did CRYO-ROP or ETROP allow estimate of recurrence after laser? Why use this outcome measure, as opposed to previous studies.
6. What is evidence for inflammation from laser causes amblyopia in second eye?
7. What does the author mean by laser causing destruction of full thickness retina?
8. Why was the outcome endpoint changed and what was the implication for statistics?

Clearly, more work remains. I think avastin can be a tremendous tool, but it is new and caution is still very much required.   We still know very little.  I hope that the patients that get avastin will have very careful examinations weekly or every two weeks until 6 month corrected and then every 2 months until 9 months corrected.  If there is a area of non-perfusion follow up need to continue for a few decades.  Regardless of my questions avastin is now a proven alternative to laser, I would recommend laser for any oddly behaving eyes after avastin until there is more experience.

Best Description of Retinopathy of Prematurity (ROP)

The NIH website has a wonderful download of an animation showing the stages of Retinopathy of prematurity. This is the Link: http://www.nei.nih.gov/rop/photos.asp.  It is described as Premature infants are at high risk for developing retinopathy of prematurity (ROP).  I have edited with iVideo and used it to explain the disease in recent lectures. At the moment I cannot seem to find the edited version.

Surgery for Retinopathy of Prematurity (ROP)

I have a very nice you tube video that shows creation of the PVD and the removal of the tractional elements.  The PVD was created only partially and then was extended using the shaking and jiggling of the  vitreous with the vitrectomy probe.  As the vitreous separated from the retina surface the tractional elements also separated.  The eye looks great with no cicatrix. This is much better in full size, I advise you goto youtube to view.  Hit the link below.



Link to:  Video of PVD and removal of tractional elements with vitrectomy

Norrie Disease Treatment

This month we reported a case of Norrie Disease that we treated at the first day of birth and was measured to have 20/100 at 2 years.  The retina remains attached.  This is the best visual results reported for Norrie Disease.  While enthusiastic I would like an opportunity to help another child and also learn if this success is repeatable.

For the details please check this months edition of Ophthalmology:  Here is the abstract.

Ophthalmology. 2010 Dec;117(12):2402-6.

Laser photocoagulation at birth prevents blindness in Norrie's disease diagnosed using amniocentesis.

Chow CC, Kiernan DF, Chau FY, Blair MP, Ticho BH, Galasso JM, Shapiro MJ.

Illinois Eye and Ear Infirmary, Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, Illinois, USA.

Abstract

OBJECTIVE: To report the first case of prophylactic laser treatment to prevent blindness in a patient who was diagnosed with Norrie's disease by genetic testing with amniocentesis.

DESIGN: Case report.

PARTICIPANTS: A 2-year-old white boy with Norrie's disease.

METHODS: A 37-week gestational age male with a family history of Norrie's disease was born via Cesarean section after the mother had undergone prenatal amniocentesis fetal-genetic testing at 23 weeks of gestation. A C520T (nonsense) mutation was found in the Norrie's disease gene. After examination under anesthesia confirmed the diagnosis on the first day of life, laser photocoagulation was applied to the avascular retina bilaterally. The patient was followed closely by ophthalmology, pediatrics, and occupational therapy departments.

MAIN OUTCOME MEASURES: Functional outcome, as documented by Teller visual acuity and formal occupational therapy testing, and anatomic outcome, as documented by Retcam photography and fluorescein angiography.

RESULTS: Complete regression of extraretinal fibrovascular proliferation was observed 1 month after laser treatment. No retinal detachment had occurred to date at 24 months. Teller visual acuity at 23 months of life was 20/100 in both eyes. The patient's vision and developmental milestones were age appropriate.

CONCLUSIONS: Pre-term genetic diagnosis with immediate laser treatment after birth may preserve vision in individuals affected with Norrie's disease.

Copyright © 2010 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.

PMID: 20619898 [PubMed - in process]


I am trying to link a pdf. for more details.  The photos may be poor quality, the Ophthalmology website is better.
 Laser for Norrie Disease PDF file

Genetic Testing for Unilateral Persistent Hyperplastic Primary Vitreous (PHPV)

Really, I love your comment.  However, I need to know is the condition mild or severe. How is the retina and macula ?

Now, to answer your question about testing for a unilateral case of Persistent Hyperplastic Primary Vitreous (PHPV) also called Persistent Fetal Vasculature Syndrome (PFVS)

This is a great question for two reasons:
1. I have found that about 20% of cases diagnosed with unilateral PHPV really have asymmetric bilateral disease.  Typically it was Familial Exudative Vitreoretinopathy (FEVR).  Therefore, I like to see a fluorescein angiogram of the periphery in both eyes.  That requires an exam asleep.  Often if the contralateral eye has significant ischemia I will treat it with laser.  this is especially an important exercise if the PHPV (PFVS) is severe and the vision is reduced. This is an example of a unilateral PHPV diagnosis. A lovely photograph that shows truncated vessel growth quire characteristic of FEVR

Figure shows the findings of FEVR in the second eye of a child diagnosed with unilateral PHPV (PFVS)

2. There are cases of FEVR that are unilateral, I would say not really that uncommon (about 10% of FEVR).  However, among FEVR appearance cases only 10% could be confused with PHPV (PFVS).  So the combination is pretty rare.  Unfortunately the genetic testing is helpful only if positive, the confidence in a negative test is not there.  Again, I like a fluorescein angiogram, but here my differentiation between unilateral PFVS (PHPV) and unilateral FEVR is still in the range of a hypothesis.

Of course the parents could get angiograms with good peripheral shots (not an easy task with typical fundus cameras) If there is a positive finding in the parents then the diagnosis is easy.